Drying is a mass transfer process resulting in the removal of water moisture by evaporation from a solid, semi-solid or liquid to end in a solid state.
A possible drying method is vacuum drying, where heat is supplied by contact conduction or radiation (or microwaves) while the produced vapor is removed by the vacuum system.
Another technique is drum drying, where a heated surface is used to provide the energy and aspirators draw the vapor outside the room.
Freeze drying or lyophilization is a drying method commonly used in the biochemical industry. The solvent is frozen prior to drying and is then sublimed, i.e., passed to the gas phase directly from the solid phase, below the melting point of the solvent. Freeze drying is often carried out under high vacuum to allow drying to proceed at a reasonable rate. Denaturation of protein and peptides can occur during freezing, leading to a freeze dried product with poor quality.
Spray drying has a wide range of application within the chemical industry, the food industry, and the biochemical and pharmaceutical industries. Spray drying has been used in the pharmaceutical industry since the early 1940's. It is a useful method for the processing of pharmaceuticals since it offers a means for obtaining powders with predetermined properties, such as particle size distribution and shape. In addition a number of formulation processes can be accomplished in one step in a spray dryer: these include encapsulation, complex formation and even polymerizations. Spray drying is also a convenient method of drying heat sensitive pharmaceuticals, such as protein drugs with minimal loss of activity.
The international patent application WO 00/00176 disclose a microparticle formulation obtainable by spray-drying a substantially pure solution of a therapeutic agent without the concomitant production of an undesirable high concentration of salt or other excipients. Salt is said to be undesirable because it has no stabilising effect, indeed the stability may be greater with reduced amounts of salt. Insulin microparticles are obtainable by dissolving Zn-insulin in acid (HCl), adding alkali (NaOH) to give an insulin solution, e.g. to a pH above 7, and spray-drying the insulin solution. The added Hydrochloric acid and Sodium hydroxide leaves the spray-dried microparticle formulation with a salt content. Further the obtained formulation will on addition to water have the same pH as the protein solution fed in the spray-dryer.
International patent publication WO 95/24183 relates to methods and compositions for pulmonary delivery of insulin. The insulin powders are produced by mixing bulk crystalline insulin in a sodium citrate buffer containing excipients (mannitol and/or raffinose) to give final solids concentration of 7.5 mg/ml and a pH of 6.7±0.3 and then spray-drying the insulin solution.
International patent publication WO 05/092301 relates to spray drying a clear solution of insulin at pH under the isoelectric point of insulin, preferably lower than 5.4.
Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized i.a. in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. GLP-1 stimulates insulin secretion in a glucose-dependant manner, stimulates insulin biosynthesis, promotes beta cell rescue, decreases glucagon secretion, gastric emptying and food intake. Human GLP-1 is hydrolysed to GLP-1(7-37) and GLP-1(7-36)-amide which are both insulinotropic peptides.
The therapeutic hormone insulin is a small protein having influence on the blood glucose level. It is daily used in the medical treatment of diabetes by millions of people. Diabetes is a chronic disease caused by absolute or relative deficiency of insulin and insulin resistance, which results in high blood glucose levels (hyperglycemia) leading to long-term complications.
Currently, the treatment of diabetes, both type 1 diabetes and type 2 diabetes, relies to an increasing extent on the so-called intensive insulin treatment. According to this regimen, the patients are treated with multiple daily insulin injections comprising one or two daily injections of long acting insulin to cover the basal insulin requirement supplemented by bolus injections of rapid acting insulin to cover the insulin requirement related to meals.
The molecule of insulin consists of two chains, A and B, with 21 and 30 residues respectively. The A chain is built up by two helical fragments separated by a short elongated part linked to one of the helices by an intra-chain disulfide bond. Two additional disulfide bonds link the A chain to the larger B chain. In the biologically active form insulin exists as a monomer in which the B chain contains a central helical region flanked by two elongated parts. In the presence of divalent ions like zinc, the monomers assemble into hexamers, where each of the two central zinc ions is coordinated by three histidine residues.
Insulin is susceptible to fibrillation, a misfolding process leading to well ordered cross-β assembly. Protection from fibrillation in βcells is provided by sequestration of the susceptible monomer within zinc hexamers. When fibrillation occurs during the spray-drying of insulin, the nozzle may clog, leading to interruptions in the drying process.
Another important factor when avoiding clogging of the spray-drying nozzles is that the protein to be dried is properly dissolved in the solution. Protein dispersed in the feed solution may also lead to clogging of the equipment.
Further the pH of the dried protein is very important. It is often desirable to obtain a dried product with a specified pH, eg. a pH comparable to physiological pH.